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Tumor Necrosis Factor--Induced Apoptosis of Human Coronary Artery Endothelial Cells: Modulation by the Peroxisome Proliferator-Activated Receptor- Ligand Pioglitazone

Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Dayuan Li, MD, PhD

Xingjian Zhang, MD

Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Jawahar L. Mehta, MD, PhD

Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 532, Little Rock, AR 72205- 7199; mehtajl{at}uams.edu

The cytokine tumor necrosis factor-a (TNF-) plays an important role in endothelial injury, which is associated with the release of reactive oxygen species and the induction of apoptosis. We report on our study of TNF--induced apoptosis in human coronary artery endothelial cells and its modulation by the peroxisome proliferator-activated receptor- (PPAR-) ligand pioglitazone. Treatment of cells with TNF- (40 ng/mL) resulted in apoptosis as measured by DNA laddering and caspase-3 activation. TNF- treatment decreased the expression of antiapoptotic protein Bcl-2 (P < .05 vs control), but not the expression of Fas or FLIP, in human coronary artery endothelial cells. Treatment of cells with TNF- also enhanced lipid peroxidation (P < .01 vs control). Pretreatment of cells with the PPAR- ligand pioglitazone blocked TNF--mediated apoptosis, caspase-3 activation, expression of Bcl-2, and lipid peroxidation (P < .01 vs TNF- alone). These results indicate that TNF- induces oxidative stress in human coronary artery endothelial cells, resulting in apoptosis through a reduction in Bcl-2 expression and the subsequent activation of caspase-3. The PPAR- ligand pioglitazone modulates lipid peroxidation, alters Bcl-2 expression and caspase-3 activation, and finally reduces apoptosis. The antioxidant and antiapoptotic effects of pioglitazone may be the mechanism by which this agent reduces endothelial injury.

Key Words: apoptosis • tumor necrosis factor- • peroxisome proliferator-activated receptor- • pioglitazone, endothelial cells

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 9, No. 1, 35-41 (2004)
DOI: 10.1177/107424840400900i106


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